(A) Field of the invention
The present invention relates to a new process for producing a calcium antagonist named as diltiazem hydrochloride. In particular, it relates to a stereo-specific synthesis of the said compound having two asymmetric carbons.
(B) Description of the Prior Art
Diltiazem hydrochloride, a benzothiazepine derivative of the formula (1), is one of the most useful of drugs which have recently been used as vasodilators especially in alleviation of anginal pains caused by angina of effort and old myocardial infarction. ##STR2##
Diltiazem hydrochloride, theoretically, is one of four optical isomers, since it has two asymmetric carbons in its molecule as seen from the above formula (1). Diltiazem hydrochloride commonly named, the most useful isomer of the four, has the (2S,3S) configuration at the asymmetric centers. In the nonstereospecific synthesis, the desired (2S,3S) isomer can be obtained at most in 25% yield. According to the known processes for production of diltiazem, the configuration corresponding to the 2 and 3 positions of diltiazem has successfully be fixed to be cis at the stage of intermediates, which however are still racemates, optically inactive, and need optical resolution with an expensive compound cinchonidine (Jap. Pat. Pub. No. 49-36221). Therefore, the optical resolution in the known process for production of diltiazem decreases the yield to 50% or below, theoretically.
Sharpless et al. described the substantial method for asymmetric epoxidation of allylic alcohols in J. Am. Chem. Soc. 102, 5974-5976 (1980), which is employed in this invention at the early stage of the process.